Methionine enkephalin regulates microglia polarization and function

Int Immunopharmacol. 2016 Nov;40:90-97. doi: 10.1016/j.intimp.2016.08.037. Epub 2016 Aug 30.


Methionine enkephalin (MENK), an opioid peptide, is known to function as a regulator in the immune system. As microglia are considered the most important immune cells in the central nervous system (CNS), we aimed to assess the function of MENK on microglia polarization and tumoricidal responses. Initially, we chose the most optimal condition of 10-12M for 48h; however, MENK had no function on the viability and apoptosis of microglia under this treatment. However, MENK treatment markedly increased levels of M1-associated genes, such as CD86, CD40, IL-12, and TNF-α, but had no effect on M2 markers, including CD163, IL-10, and TGF-β. Moreover, microglia in the MENK-treated group showed high phagocytosis capacity, which coincided with characteristics of M1 microglia. MENK stimulation also induced up-regulation of reactive oxygen species (ROS) expression, which contributed to maintaining homeostasis. We also detected NO production by measuring the end product nitrite, and found that MENK treatment increased expression of nitrite and inducible NO synthase (iNOS), but did not influence arginase-1 (Arg1) expression. Furthermore, treatment of microglia with MENK led to a significant increase in cytotoxicity against glioblastoma cells, indicating that MENK possessed anti-tumor ability. Overall, MENK treatment could induce microglia to an M1 phenotype, modulating Th1 responses in the immune system. Additionally, microglia treated with MENK had tumoricidal activity, which provides new insight into anti-tumor immunity.

Keywords: Anti-tumor immunity; Methionine enkephalin; Microglia; Polarization.

MeSH terms

  • Antigens, CD / genetics
  • Apoptosis / drug effects
  • Arginase / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Enkephalin, Methionine / pharmacology*
  • Glioblastoma
  • Humans
  • Microglia / drug effects*
  • Microglia / immunology*
  • Microglia / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Phagocytosis / drug effects
  • Reactive Oxygen Species / metabolism


  • Antigens, CD
  • Cytokines
  • Reactive Oxygen Species
  • Enkephalin, Methionine
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Arginase
  • arginase I, human